Increasing emphasis has been placed on the role of the serotonin 5-HT2A receptor in the pathogenesis of schizophrenia and affective disorders. In particular, the therapeutic effects of antipsychotic drugs have been suggested to be due to their actions at the 5-HT2A receptor that lead to changes in receptor density. However, the functional consequences of such receptor changes have not been fully examined. The innovative aspect of this proposal derives from: 1) our use of an animal model in which associative learning (a process that is abnormal in schizophrenia) is regulated by the 5-HT2A receptor, 2) our ability to detect changes in learning that result from alterations in the density of the 5-HT2A receptor in the adult brain, and 3) our preliminary evidence that the 5-HT2A receptor is constitutively active. We now propose to examine in detail how both the up- and down- regulation of the 5-HT2A receptor in limbic cortex, brain regions that are thought to be affected in schizophrenia, alters the rate of learning, the neuronal circuitry within those brain regions, the development of long-term potentiation (an in vitro model of learning), the constitutive activity of the receptor, and receptor mediated second messenger signaling. Learning is measured during classical trace conditioning of the rabbit's eye-blink response, a form of learning that is regulated by the 5-HT2A receptor, and is dependent on the integrity of limbic cortex (hippocampus and frontal cortex). It is important to note that eyeblink conditioning is also impaired in schizophrenia. Intracerebral injections of drugs will be used to identify the critical brain loci at which the 5-HT2A receptors regulate learning. Depletions of brain serotonin will be employed to determine the extent of constitutive activity at the 5-HT2A receptor as measured by basal and agonist stimulated second messenger signalling. The results of this research should provide novel therapeutic strategies in the treatment of schizophrenia. In addition, this research will provide a new perspective and new insights into the neurobiology of learning.